Thesis (Th. D.)--Grace Theological Seminary, 1967. / Includes bibliographical references (leaves [199]-202).

Cornelius Van Til is known for his work in the field of apologetics. His distinctive approach emphasized consistency between methodology and theology in order to defend the Christian faith. Though often neglected, his doctrine of God provided the foundation for his methodology. The nature of who God is informs how we know him and how we interpret his word. The three most prominent contours of his doctrine were: the Creator-creature distinction, incomprehensibility, and the ontological Trinity. The value of these particular emphases is that they are key touchpoints for diagnosing apologetic methods and affirming the Christian system of truth. The nature of his assessment of methodology at the worldview level along these contours has wide-ranging implications for other disciplines, including hermeneutics. The following study explores the relevance of Van Til’s doctrine of God for contemporary biblical hermeneutics in terms of consistency between method and theology proper as revealed in the Bible. Van Til’s doctrine of God is relevant for contemporary hermeneutics both, in how ‘hermeneutics’ has come to be defined and in terms of how its relationship to metaphysics has been understood. In the former, there has been movement toward a more explicitly holistic definition, one that provides a general theory of understanding involving worldview assumptions. In the latter, the relationship between hermeneutics and metaphysics has been unavoidable. It has also been unstable and inconsistent. Van Til speaks to each of these trends from a self-conscious, Christian worldview. His work focused on worldview considerations and presuppositions, including metaphysical and epistemological concerns. It is argued that Van Til’s contributions are not only relevant for evaluating hermeneutical methods, but also contribute to some concerns of recent developments in the field. Two such developments which have influenced evangelical hermeneutics are Speech Act Theory (SAT) and Theological Interpretation of Scripture (TIS). Van Til’s contributions strengthen the effort to give due consideration to the divine author in discussions of meaning and method, but also serve to help critically evaluate and round out both. Lastly, the relevance of his theology proper is seen regarding the contemporary hermeneutical issue of the NT use of the OT. This provides a brief case study concerning a prominent contemporary issue in evangelical hermeneutics. Van Til’s contribution asks deeper questions regarding method and meaning which further the discussion, and detects flaws in some attempts to make sense of how the NT uses the OT.

De nombreuses études en oncoimmunologie portent sur l’échec immunitaire dans le contexte de progression tumorale, mais elles sont plus rares à porter sur un contexte de régression, lorsque le système immunitaire est efficace. De ce fait, bien souvent la littérature met en avant le rôle cytotoxique des lymphocytes T CD8+, ou bien leur anergie dans le contexte de progression tumorale, causée par des cellules myéloïdes telles que les MDSC ou les macrophages de phénotypes M2, considérés comme pro-tumoraux. J’ai pour ma part étudié la réponse immunitaire dans le cadre d’une régression tumorale. Des cellules TC1 transplantées en s.c. dans des souris C57BL6/J, donnent des tumeurs solides d’environ 6mm de diamètre 11 jours plus tard. A ce moment là (J0), les souris sont vaccinées à proximité de la tumeur (priming), par un vaccin contenant la sous-unité B non toxique de la Shiga toxine couplée au peptide E7 de l’HPV16 (exprimé par les TC1), combiné à de l’IFNα. Une semaine plus tard (J7), un « boost » est effectué. Après le boost, la croissance tumorale cesse puis la tumeur régresse. L’analyse cinétique par cytométrie révèle un infiltrat immunitaire important pendant, et précédant la régression tumorale. La nature de cette infiltrat varie avec le temps. A J5, un infiltrat myéloïde est observé, suivi d’un infiltrat lymphocytaire à partir de J8. Une déplétion des cellules T CD8+ inhibe la régression tumorale, alors que dans les souris CXCR3-/-, dans lesquelles les CD8+ ne sont pas déplétés mais leur recrutement est fortement affecté, une régréssion tumorale est possible malgré un infiltrat T CD8+ très faible. Cela laisse penser que d’autres acteurs que les LT cytotoxiques sont nécessaires à la régression tumorale, comme probablement les cellules myéloïdes qui infiltrent le tumeur avant les cellules T. L’analyse de cette population montre une activation des monocytes et macrophages (MHC II+), avec un pic d’activation autour de J9, au début de la régression. La capacité cytotoxique de ces cellules, mesurée in vitro par immunofluorescence est augmentée comparée à des myéloïdes isolées de tumeurs de souris en progression. De plus, l’ajout d’un anticorps anti-TNFα inhibe partiellement cette cytotoxicité. Cela montre qu’après vaccination, les monocytes/macrophages sont capables de tuer les cellules tumorales. Une déplétion partielle des macrophages au moment de la vaccination, à l’aide du PLX3397 (inhibiteur du CSF1R), réduit l'efficacité de la vaccination. Les cellules myéloïdes, lorsqu'elles sont présentes, contribuent fortement à la régression tumorale induit par le vaccin composite, et leur action implique probablement des interactions avec les LT CD8+. C'est ce que suggère l'observation de tumeurs vaccinées dans des souris IFNϒ-/-, dans lesquelles l'efficacité vaccinale est aussi inhibée. Cette thèse montre qu’après une stimulation appropriée, qui peut, comme ici, mimer une infection virale, les cellules myéloïdes peuvent participer activement à la régression tumorale. / Most oncoimmunology studies are performed in an immune failure context of progressing tumor. They rarely describe tumor regressions, when the immune response is efficient. As a result, the literature tends to highlight the cytotoxic role of CD8+ T cell or their anergy in the context of tumor progression, caused by myeloid cells such as the MDSC or M2 polarized macrophages, considered as protumoral. My PhD work has been focused on the immune response in a context of tumor regression. TC1 cells transplanted s.c. in C57 BL6 J mice, give rise to solid tumors of approximately 6 mm diameter 11 days later. At that time (day 0), mice are vaccinated peritumorally for a priming with a composite vaccine containing the subunit B of the Shiga toxin coupled to E7 peptide from HPV16 (present on TC1), combined with the IFNα. A week later (day 7), a boost is made. After the boost, tumor growth stops and the tumor regress. Kinetic cytometric analysis revealed a significant immune infiltrate during and prior to tumor regression. The nature of this infiltrate varies with time. On day 5, a myeloid infiltrate is observed, followed by a lymphocytic infiltrate which is conspicuous after day 8. Depletion of CD8+ T cells inhibits tumor regression, while in CXCR3- /- mice, in which the CD8+ are not depleted but their recruitment is severely affected, tumor regression is possible despite a very low CD8+ T cell infiltrate. This suggests that some effectors, other than cytotoxic T cells, are required for tumor regression, including probably myeloid cells that infiltrate the tumor before T cells. The analysis of this population shows an activation of monocytes and macrophages (MHC II+) with a peak of activation around day 9, early in the regression. The cytotoxic capacity of these cells was tested in vitro, by depositing F4/80+ cells from vaccinated tumors or not, on a TC1 cell monolayers in culture. Only myeloid cells from vaccinated tumors appear to kill tumor cells, and adding an anti-TNFα inhibits this cytotoxicity. This shows that after immunization, monocytes/macrophages are capable of killing tumor cells. A partial depletion of macrophages at the time of vaccination, after treatment with PLX3397 (CSF1R inhibitor), reduces the vaccine efficacy. Myeloid cells contribute significantly to the observed tumor regression, and their action involves interactions with CD8+ T cells. This hypothesis is consistent with the observation of tumors in vaccinated IFNϒ- /- mice, in which the vaccine efficacy is also inhibited. This thesis shows that after an appropriate stimulation, for instance, here, by mimicking a viral infection, myeloid cells can actively participate in tumor regression.

Memoria para optar al Título Profesional de Ingeniero Forestal

The purpose of reformed apologetics is to defend the Christian faith against heresy.However, this is not all. Reformed apologetics also wants to give a convincing answer why the Christian view is the real hope for mankind (see 1 Peter 3:15).Other that differ from this life and world view, do it mostly based on a different starting point. Although finer points are debated between parties, the starting point, including presuppositions, are always somewhere in the background. Van Til4 and Stoker5, two famous Reformed thinkersof the last century (respectively theological and philosophical), in contact with other made their presuppositions part of their apologetic discussions. This agreement in approach and method emerges in the Festschrift for Van Til, when Stoker (1971:28-71) proposes a connection between his and Van Til’s methods, and when Van Til in turn responds positively. This study will focus on what role these two thinkers’ presuppositions play in their apologetic conversation. It eventually comes to important guidelines regarding the place and role of presuppositions in conversations of Christians across a broad scientific front with those who hold other points of departure. / MTh (Missiology), North-West University, Potchefstroom Campus, 2014

The purpose of reformed apologetics is to defend the Christian faith against heresy.However, this is not all. Reformed apologetics also wants to give a convincing answer why the Christian view is the real hope for mankind (see 1 Peter 3:15).Other that differ from this life and world view, do it mostly based on a different starting point. Although finer points are debated between parties, the starting point, including presuppositions, are always somewhere in the background. Van Til4 and Stoker5, two famous Reformed thinkersof the last century (respectively theological and philosophical), in contact with other made their presuppositions part of their apologetic discussions. This agreement in approach and method emerges in the Festschrift for Van Til, when Stoker (1971:28-71) proposes a connection between his and Van Til’s methods, and when Van Til in turn responds positively. This study will focus on what role these two thinkers’ presuppositions play in their apologetic conversation. It eventually comes to important guidelines regarding the place and role of presuppositions in conversations of Christians across a broad scientific front with those who hold other points of departure. / MTh (Missiology), North-West University, Potchefstroom Campus, 2014

The immunogenicity of breast cancer (BC) is quite heterogeneous among the clinical subtypes, with immune responses identified most frequently in triple negative (TNBC) and HER2-positive tumors. The extent, spatial localization, distribution patterns, organization and phenotype of the BC immune infiltrate are currently being widely investigated but require standardization before they can be used clinically. One highly relevant unmet clinical need is to understand how immune features are linked to prognosis and potential benefit from treatments, particularly immunotherapy. The present work investigated tumor-infiltrating lymphocytes (TIL), tertiary lymphoid structures (TLS), the expression of multiple targetable inhibitory immune checkpoint molecules (PD-1, PD-L1 and PD-L2, CTLA-4, LAG3 and TIM3) and their clinical relevance in primary BC. Different technical approaches were employed including: flow cytometry (FC) on fresh tissue homogenates; immunohistochemistry (IHC) and immunofluorescence (IF) on formalin-fixed paraffin embedded (FFPE) tissue blocks from untreated primary tumors; and gene expression on a large dataset of BC patients with available long-term survival data. Flow cytometric analysis of PD-1 expression and its principal ligands PD-L1 and PD-L2 together with CTLA-4, LAG3 and TIM3 on TIL in fresh untreated primary tumors revealed that PD-1 and CTLA-4 are most highly expressed on BC TIL and PD-L1 is the principal PD-1 ligand in BC. Immune checkpoint molecule expression parallels the extent of TIL infiltration and TLS presence and number, with the patterns detected similar to that observed in secondary lymphoid organs. Significantly improved disease-specific survival (DSS) has been associated with PD-1hi HER2-enriched and PD-L1hi, PD-L2hi and CTLA-4hi basal-like BC; however there is significant heterogeneity between individual tumors even within the same subtype. These observations suggest that determining expression levels of multiple targetable inhibitory immune checkpoint molecules in patients might help to successfully target them in BC patients most likely to respond.We examined the concordance between two experienced immuno-pathologists who read 800 IHC-stained slides from five independent series over a period of four years to determine the reproducibility of assessing multiple immune biomarkers. This included scoring TIL, TLS, PD-1 and PD-L1 together with detailed information on the spatial localization and cell types expressing these molecules in the tumor microenvironment (TME). The interobserver reproducibility for the assessment of TIL and TLS was consistently good to excellent overtime, while the concordance for PD-L1 evaluation ranged from fair to excellent when it was only expressed on tumor cells (TC); and the concordance for PD-1 evaluation was fair to excellent when it was expressed in TLS and evaluated in primary tumors. Neither PD-L1 expression by TC, nor PD-1 expression within a TLS was significantly associated with prognosis in our datasets.The extent of TIL, TLS and PD-1 and PD-L1 expression were studied in a cohort of TNBC patients who underwent genetic counseling for their personal/familial history of BC or ovarian cancer (OC). This study revealed a remarkable similarity in patterns of immune infiltration between the two cohorts. Interestingly, a higher prevalence of TIL intermediate cases (≥10% and <50% TIL) was detected in the BRCA-mutated cohort, suggesting that this group may be more immunogenic.We next investigated whether the extent and presence of these immune parameters were associated with prognosis in the most highly infiltrated, aggressive BC subtypes (TNBC and HER2-positive). We determined the ideal cut-off for each subtype (TNBC and HER2-positive) to use TIL as a categorical variable. This study found a consistent prognostic impact from TIL (in any tumor compartment including stromal, intratumoral and global areas) and a novel association between PD-L1 expression within TLS and better survival in TNBC. This last effect was driven by baseline stromal TIL, strengthening the importance of reliably quantifying the levels of TIL in BC. Overall, our analyses show that among the targetable inhibitory immune checkpoint molecules investigated in BC, PD-1 and CTLA-4 are most highly expressed by BC TIL and are associated with higher infiltration of TIL; PD-L1 is the principal ligand for PD-1; TIL and TLS are reproducibly scored on IHC-stained tissues; and TIL levels are associated with a better prognosis in TNBC independent of their location in the TME at optimal cut-offs. Our data also provide new insight on targetable inhibitory immune checkpoint molecule expression and location as well as showing a prognostic role for TIL assessed by IHC in primary BC, which identifies these biomarkers as ideal candidates for further investigation. / Doctorat en Sciences médicales (Médecine) / info:eu-repo/semantics/nonPublished

<p>Syftet med undersökningen är att ta reda på hur man arbetar med TIL- programmet i kommunens olika skolor och här även göra en jämförande studie. Med denna metod vill man på ett tidigt stadium upptäcka och påbörja arbete med de elever som behöver extra hjälp med läsinlärning. Jag har inlett mitt arbete med en presentation av olika metoder inom läsinlärning i den svenska skolan. Här presenteras även TIL- programmet. Som metod har jag använt kvalitativa intervjuer med sex pedagoger, specialläraren på varje skola inom kommunen på grundskolans tidigare år. Resultatet påvisade att där läraren följde TIL- programmet framkom ett tydligare positivt resultat. Slutsatsen är att man följer metoden olika mycket i skolorna och ju mer programmet följdes, desto tydligare och snabbare positiva resultat.</p><p> </p>

Syftet med undersökningen är att ta reda på hur man arbetar med TIL- programmet i kommunens olika skolor och här även göra en jämförande studie. Med denna metod vill man på ett tidigt stadium upptäcka och påbörja arbete med de elever som behöver extra hjälp med läsinlärning. Jag har inlett mitt arbete med en presentation av olika metoder inom läsinlärning i den svenska skolan. Här presenteras även TIL- programmet. Som metod har jag använt kvalitativa intervjuer med sex pedagoger, specialläraren på varje skola inom kommunen på grundskolans tidigare år. Resultatet påvisade att där läraren följde TIL- programmet framkom ett tydligare positivt resultat. Slutsatsen är att man följer metoden olika mycket i skolorna och ju mer programmet följdes, desto tydligare och snabbare positiva resultat.

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